Treatment of inflammatory bowel disease
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Treatment of inflammatory bowel disease . Goals of treatment. Goals of Treatment. Asacol ®. AZO-COMPOUNDS. Stomach. Small Intestine. Large Intestine. Mesalamine w/ eudragit-S. Azo bond. Oral 5-ASA Release Sites. Pentasa ® . Mesalamine in microgranules. Aminosalicylate.

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Oral 5 asa release sites

Asacol®

AZO-COMPOUNDS

Stomach

Small Intestine

Large Intestine

Mesalamine

w/ eudragit-S

Azo bond

Oral 5-ASA Release Sites

Pentasa®

Mesalamine in microgranules


Aminosalicylate
Aminosalicylate

  • Well established role in induction and maintaining remission in UC

  • Dose –related effect in UC

  • Long term safety established

  • Efficacy in crohn’s disease is controversial due to absence of rigorous evidence and preponderance of negative studies




Definitions
Definitions

  • Corticosteroid refractory disease

    • Patients who have active disease despite prednisolone up to 0.75 mg/kg/day over a period of four weeks.

  • Corticosteroid dependent disease; Patients who are either

    • (a) unable to reduce corticosteroids below the equivalent of prednisolone 10 mg/day (or budesonide below 3 mg/day) within three months of starting corticosteroids, without recurrent active disease, or

    • (b) who have a relapse within three months of stopping corticosteroids.

The aim should be to withdraw corticosteroids completely.

E F Stange, S P L Travis; ECCO Consensus on the diag&Mang of CD”Gut 2006;55(Suppl I.)


Steroids2
Steroids

  • Crohn’s disease: 50% of patients will require treatment with steroids.

  • Of those 28% will become steroid dependent

  • Ulcerative colitis: 34% of patients will require treatment with steroids.

  • Of those 22% will become steroid dependent


Steroid
Steroid

  • Effective for the short-term control of symptoms of Crohn's disease but are neither effective nor safe for long-term maintenance of response.

  • In patients with disease that is refractory to or dependent on glucocorticoids, steroid-sparing strategies should be considered, including immune modulators or surgery.




Immunomodulators azathioprine and 6 mercaptopurine
Immunomodulators: azathioprine and 6 -mercaptopurine



Safety and tolerability
Safety and tolerability

  • Flu like symptoms occuring after 2-3 weeks and resolve on discontinuation of RX (20%)

  • Hepatotoxicity and pancreatitis(<5%)

  • Leukopenia(<3%)

  • Good long term tolerance

  • Can be given during pregnancy

  • ? ↑ risk of neoplasm



Cyclosporine
Cyclosporine

  • Competetively binds to and inhibit calmodulin dependent calcineurin, leading to suppression of T-cell and IG E receptor signaling pathways.

  • IV Cyclosporine has a rapid onset of action

  • Neither intravenous nor oral low-dose cyclosporine has proven efficacy in patients with luminal CD.

  • High toxicity limiting its use








Mild to moderate distal colitis induction of remission
Mild to moderate distal colitis: induction of remission

  • Topical 5 –ASA is more effective than topical steroid and oral 5-ASA

  • Combination of oral and topical 5-ASA is more effective than either alone

  • Patient unresponsive to topical therapy: po steroids


Mild to moderate distal colitis maintenance of remission
Mild to moderate distal colitis: maintenance of remission induction of remission

  • Topical and oral 5-ASA :Effective in maintainaing remission

  • Combination of oral and topical 5-ASA is more effective than oral 5-ASA alone

  • Topical and oral steroid: no role


Mild to moderate extensive colitis induction of remission
Mild to moderate extensive colitis: induction of remission induction of remission

  • Oral 5-ASA is the first line of therapy

  • Oral steroids are reserved for: - refractory patients to PO +/- topical 5-ASA - troubling sxs requiring rapid improvement


Mild to moderate extensive colitis maintenance of remission
Mild to moderate extensive colitis: maintenance of remission

  • All 5 –ASA are effective in preventing relapse

  • Azathioprine or 6-MP may be used: -steroid sparing agent in steroid dependent patients -steroid refractory patients who are not acutely ill -remission not adequately maintained on 5-ASA


Management of severe colitis
Management of severe colitis

  • Patients with severe colitis refractory to maximal oral prednisone, oral 5-ASA and topical RX, or presents with toxicity should be hospitalized for IV steroids

  • Patients not responding within 7-10 days of maximal medical therapy should be offered alternative treatment: -biologic treatment -cyclosporin- surgery


Cyclosporine1
Cyclosporine

  • Cyclosporine has a rapid onset of action (more rapid than AZA, 6-MP, or methotrexate) and when administered intravenously has been shown to be effective in the management of patients with severe UC.

  • It often demonstrates clinical efficacy within 1 week when administered intravenously.

  • Oral cyclosporine has a possible role in the induction of a clinical response in UC and short term in the maintenance of an intravenous cyclosporine-induced response, allowing time for the slow-acting purine analogues to become effective.


Biologic treatment1
Biologic treatment

  • Infliximab is the only FDA approved treatment for patients with moderate-severe ulcerative colitis

  • ACT 1 study: treatment with infliximab can prevent hospitalizations and surgery for UC patients in the first year of treatment


Ulcerative Colitis: Mild to Moderate

Acute flare

Exclude entericpathogen

Extensive

Left side

Oral 5-ASA

Patient willing totake rectal therapy

Patient unwilling to take rectal therapy

Consider rectal therapy(5-ASA and/or steroid)

Maintain

Maintainoral 5-ASA

Oral steroid

Responseadequate

Responseinadequate

Response adequate

Considerincreased dose

Response

inadequate

Oral 5-ASA

Responseinadequate

Responseadequate

Response

inadequate


Ulcerative Colitis: Moderate to Severe

Moderate

Severe

Infliximab

IV Steroid

ConsiderCyA

Oral steroid

6MP/AZA

Taper

Success

Colectomy

Successful

Maintain on5-ASA and observe

Maintaininfliximab

Maintain6-MP/AZA

Inadequate response

Inadequate response

Adequate response

Response

Unsuccessful

No

response

Failure

No

response

Response


Therapeutic Pyramid for

Active UC

Severe

Surgery

Cyclosporine

Infliximab

Moderate

Systemic Corticosteroids

AZA/6-MP

Oral Steroids

Mild

Aminosalicylates


Indication for surgery
Indication for surgery

  • Total colectomy with ileoanal pouch anastomosis is the procedure of choice for patients with UC:


Indications for surgery in uc
Indications for surgery in UC

Analysis of 917 UC patients at Heidelberg University between 1982 and 2001

Perforation

6%

Toxic uc

10%

Colorectal ca 7%

Dysplasia 3%

Failure of

medical therapy

74%

Hoffmann et al. Chronisch-Entzündliche Darmerkrankungen. Thieme 2004


Potential complications of uc surgery
Potential Complications of UC Surgery

  • 3-10 stools/24 hrs 1

  • Decrease in female fertility (38-54%)3-5

  • Pouchitis (10-60%)1

  • Small bowel obstruction (20%)1

  • Abscesses & fistulae (5-12%)6

  • Pouch-vaginal fistula (4%)1

  • Long-term continence problems (15%)6

  • Impotence (1.5%)2

1Sagar PM, Pemberton JH. In Satsangi J, Sutherland L, et al, eds. Inflammatory Bowel Diseases. Spain: Elsevier Limited; 2003:491 511.

2Pemberton JH, et al. Ann. Surg. 1987;206(4):504-513. 3Olsen, KO, et al. Gastroenterology. 2002;122:15-19.

4Johnson P, et al. Dis Colon Rectum. 2004;47;1119–1126. 5Gorgun E, et al. Surgery. 2004;136(4):795–803.

6Stange et al. Colitis ulcerosa – Morbus Crohn.Uni-Med Verlag AG 1999.


Pouchitis
Pouchitis

  • Idiopathic inflammation of “pouch” after ileoanal pouch anastomosis


Treatment of crohn s disease

Treatment of crohn’s disease


Mild to moderate luminal active disease
Mild to moderate luminal active disease

  • Despite the use of oral mesalamine treatment in the past, new evidence suggests that this approach is minimally effective as compared with placebo and less effective than budesonideor conventional corticosteroids


5 asa in crohn s disease
5-ASA in crohn’s disease

  • No mesalamine product has been FDA approved for either induction or maintenance of remission

  • Not effective in maintaining post-operative remission.


Mild to moderate luminal active disease1
Mild to moderate luminal active disease

  • Oral budesonide is more effective than placebo, or 5-ASA and have similar efficacy to conventional po steroids for the treatment of mild-moderate active CD involving distal ileum and/or right colon.

  • Budesonide is recommended for use as primary therapy for patients with mild to moderate active CD localized to ileum and/or right colon


Moderate to severe luminal disease
Moderate to severe luminal disease

  • Prednisone (40 -60 mg/day) until resolution of symptoms

  • Infection or abscess requires antibiotic therapy or drainage

  • Azathioprine and 6-MP are effective in maintaining a steroid-induced remission

  • Parenteralmethotrexate (25 mg/week) :effective for steroid-dependent and steroid-refractory CD


Biologic treatment2
Biologic treatment

  • Anti TNF monoclonal Ab : infliximab, adalimunab and cetrolizumab are effective for: -moderate- severely active CD not responding despite complete and adequate therapy with a steroids or immunosuppressive agent -as alternative to steroid therapy in selected patients in whom steroid is contraindicated

  • The anti-alpha 4 integrinAb : natalizumab, is effective for patients with moderate to severely active disease who had an inadequate response to anti TNF AB or unable to tolerate it


Therapeutic strategies step up
Therapeutic Strategies: Step up

Sequential escalation based upon symptoms, usually starting with the

efficacysafest medication but with the least

Most prevalent strategy

Advantages: minimize risks of adverse drugs effects

Disadvantages: risk of inadequate treatment, not targeting

the underlying process, i.e. the inflammation and the

potential complications



Therapeutic strategies top down
Therapeutic Strategies: Top down

Therapy with a potent agent since the beginning

Advantages: strong suppression of inflammation

from diagnosis

Disadvantages: Expensive, treats all patients as if

they have identical risk and lead to unnecessary

exposure to adverse drug effects


Treatment of perianal fistula
Treatment of perianal fistula

  • Mesalamine:

  • No clinical trial has demonstrated any beneficial effect of mesalazine on fistula healing.

  • Steroids:

  • Not effective


Treatment of perianal fistula1
Treatment of perianal fistula

  • Antibiotics: widely used first-line treatment for fistulas in patients with Crohn’s disease

  • Dual role in the treatment of fistulas: as a primary therapy and as an adjuvant therapy for abscesses and infections caused by the fistula.

  • Metronidazole:

  • Most studied antibiotic

  • Fistulas generally respond to administration of this antibiotic after 6–8 weeks, but therapy is typically continued for 3–4 months.

  • Ciprofloxacin:

  • The beneficial effects of the fluoroquinolone antibiotic, ciprofloxacin, have demonstrated in various studies.

  • combination treatment with metronidazoleand ciprofloxacin has shown beneficial effects


Treatment of perianal fistula2
Treatment of perianal fistula

  • Immunosuppressives:

  • Azathioprine and 6-mercaptopurine: seem to be effective treatments for perianal fistulas

  • Methotrexate: Not recommended

  • Cyclosporin: Not recommended


Treatment of perianal fistula3
Treatment of perianal fistula

  • Biologic: In contrast to azathioprine and 6- MP, the clinical effects of biologics begin to be seen soon after initiation of therapy

  • Surgery:

  • The reported incidence of perianal fistulas that require surgery in patients with Crohn’s disease varies from 25–30%.

  • The goals of surgery in these patients are to cure the fistula(s) while preserving anal sphincter function.


Treatment of internal fistula
Treatment of internal fistula

  • If asymptomatic: no need for tratment

  • Symptomatic :surgical resection of diseased bowel segment



Indication of surgery in crohn s disease
Indication of surgery in crohn’s disease

  • Surgical resection, stricturoplasty, or drainage of abscesses is indicated to treat complications or medically refractory disease

  • Surgical resection rarely “ cures ” CD

  • Nevertheless, surgical intervention is required in up to two thirds of patients

  • The most common indications for surgical resection are refractory disease despite medical therapy or side effects of medication (steroid dependence)




Stricturoplasty
Stricturoplasty

  • Stricturoplasty has been advocated as an important alternative to resection in the treatment of selected fibrotic strictures of the small bowel and should be attempted when possible to help avoid: - impaired nutrient absorption -steatorrhea -bacterial overgrowth -short bowel syndrome



Cancer in crohn s disease
Cancer in crohn’s disease

  • When Crohn's disease involves the large bowel, the excess risk of colorectal cancer appears to be similar to that in ulcerative colitis of similar extent.

  • The characteristics and prognosis of colorectal cancer in Crohn's disease also are similar to those for colorectal cancer in ulcerative colitis.

  • surveillance colonoscopy has been recommended as a means of early detection.



Colorectal cancer in ulcerative colitis
Colorectal cancer in ulcerative colitis

  • Patients with UC have an increased risk of colorectal cancer.

  • This risk is dependent on several factors

  • the most important -duration -extent of disease

  • Other risk factors : -PSC -family history of colon cancer -age at diagnosis of disease -severity of inflammation


Risk factors for colon cancer in ulcerative colitis and crohn s colitis
Risk Factors for Colon Cancer in Ulcerative Colitis and Crohn’s colitis

Importance

Risk Factor

Choi PM, et al. Gastroenterol Clin North Am 1995;24:671-87.

Eaden J. Am J Gastroenterol 2000;95:2710-2719.


Ekbom, et al NEJM, 1990


Colorectal cancer in ulcerative colitis1
Colorectal cancer in ulcerative colitis

  • The incidence of colon cancer in UC has been estimated at approximately 7% to 10% at 20 years of disease and as high as 30% after 35 years of disease.

  • in general, the risk of CRC may be estimated to increase within the range of 0.5% to 1.0% per year after 8 to 10 years of disease in patients with extensive UC




Future of ibd treatment
Future of IBD treatment

  • 5 ASA will be administered once daily in ulcerative colitis , and decrease in crohn’sdisaease

  • Treatment of IBD with steroids will decrease due to lack of long term efficacy and side effects

  • The use of anti-TNF therapy will most likely increase

  • They will be used earlier in the course of CD with more rigorous treatment goal: mucosal healing


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